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- Title
248. Revealing the Role(s) of TNF-alpha in Early Alzheimer's Disease Via rAAV-Mediated Hippocampal Gene Transfer in a Triple Transgenic Mouse Model<sup>*</sup>.
- Authors
Janelsins, Michelle C.; Mastrangelo, Michael A.; Park, Keigan M.; Fowlkes, Kelly L.; Kinsky, Maria; Narrow, Wade C.; Oddo, Salvatore; LaFerla, Frank M.; Federoff, Howard J.; Bowers, William J.
- Abstract
Alzheimer's disease is a complex neurodegenerative disorder that drastically impairs intellectual and emotional functioning in afflicted individuals. The disease is characterized pathologically by a temporal and spatial progression of amyloid-beta (Aβ) deposition, neurofibrillary tangle formation, and synaptic degeneration. Inflammatory mediators have long been proposed as being integral for initiating and/or propagating AD-associated pathologic processes within the brain. To this end, we assessed the expression of proinflammatory molecules in the recently described triple transgenic mouse model (3xTg-AD), which exhibits Aβ deposition, neurofibrillary tangle formation, and synaptic dysfunction with regional specificity similar to human AD. We observed significant up-regulation of the pro-inflammatory cytokine, TNF-α, specifically within one of the earliest affected brain regions in AD, the entorhinal cortex, prior to the onset of overt amyloid pathology. Moreover, the 3xTg-AD entorhinal cortex, unlike the hippocampus, harbored an increased number of microglia/macrophages as determined by quantification of F4/80-positive cells, further implicating the entorhinal cortex in inflammatory processes at early stages of the disease. A recombinant adeno-associated virus (rAAV) vector expressing TNF-α to create a sustained focal inflammatory response was stereotactically delivered to 3xTg-AD mice prior to the appearance of pathological signatures. In ongoing studies, we have observed significant alterations in downstream TNF-α related signaling molecule expression in transduced brain tissues and concomitant modulation of memory/learning behaviors. This integrated biochemical, immunohistochemical, and behavioral approach will provide major insights into the involvement of TNF-α mediated inflammation in the temporal and spatial progression of early AD pathogenic events and carries the potential to reveal new therapeutic targets.Molecular Therapy (2006) 13, S95–S95; doi: 10.1016/j.ymthe.2006.08.275
- Subjects
ALZHEIMER'S disease; TRANSGENIC animals; GENETIC transformation; TRANSGENIC mice; GLYCOPROTEINS
- Publication
Molecular Therapy, 2006, Vol 13, pS95
- ISSN
1525-0016
- Publication type
Article
- DOI
10.1016/j.ymthe.2006.08.275